Rafailidis, N. | Search bioRxiv

bioRxiv2024

Annotation Vocabulary (Might Be) All You Need

Protein Language Models (pLMs) have revolutionized the computational modeling of protein systems, building numerical embeddings that are centered around structural features. To enhance the breadth of biochemically relevant properties available in protein embeddings, we engineered the Annotation Vocabulary, a transformer readable language of protein properties defined by structured ontologies. We trained Annotation Transformers (AT) from the ground up to recover masked protein property inputs without reference to amino acid sequences, building a new numerical feature space on protein descriptions alone. We leverage AT representations in various model architectures, for both protein representation and generation. To showcase the merit of Annotation Vocabulary integration, we performed 515 diverse downstream experiments. Using a novel loss function and only $3 in commercial compute, our premier representation model CAMP produces state-of-the-art embeddings for five out of 15 common datasets with competitive performance on the rest; highlighting the computational efficiency of latent space curation with Annotation Vocabulary. To standardize the comparison of de novo generated protein sequences, we suggest a new sequence alignment-based score that is more flexible and biologically relevant than traditional language modeling metrics. Our generative model, GSM, produces high alignment scores from annotation-only prompts with a BERT-like generation scheme. Of particular note, many GSM hallucinations return statistically significant BLAST hits, where enrichment analysis shows properties matching the annotation prompt even when the ground truth has low sequence identity to the entire training set. Overall, the Annotation Vocabulary toolbox presents a promising pathway to replace traditional tokens with members of ontologies and knowledge graphs, enhancing transformer models in specific domains. The concise, accurate, and efficient descriptions of proteins by the Annotation Vocabulary offers a novel way to build numerical representations of proteins for protein annotation and design.

bioinformatics↗

bioRxiv2023

cdsBERT - Extending Protein Language Models with Codon Awareness

AO_SCPLOWBSTRACTC_SCPLOWRecent advancements in Protein Language Models (pLMs) have enabled high-throughput analysis of proteins through primary sequence alone. At the same time, newfound evidence illustrates that codon usage bias is remarkably predictive and can even change the final structure of a protein. Here, we explore these findings by extending the traditional vocabulary of pLMs from amino acids to codons to encapsulate more information inside CoDing Sequences (CDS). We build upon traditional transfer learning techniques with a novel pipeline of token embedding matrix seeding, masked language modeling, and student-teacher knowledge distillation, called MELD. This transformed the pretrained ProtBERT into cdsBERT; a pLM with a codon vocabulary trained on a massive corpus of CDS. Interestingly, cdsBERT variants produced a highly biochemically relevant latent space, outperforming their amino acid-based counterparts on enzyme commission number prediction. Further analysis revealed that synonymous codon token embeddings moved distinctly in the embedding space, showcasing unique additions of information across broad phylogeny inside these traditionally "silent" mutations. This embedding movement correlated significantly with average usage bias across phylogeny. Future fine-tuned organism-specific codon pLMs may potentially have a more significant increase in codon usage fidelity. This work enables an exciting potential in using the codon vocabulary to improve current state-of-the-art structure and function prediction that necessitates the creation of a codon pLM foundation model alongside the addition of high-quality CDS to large-scale protein databases.

bioinformatics↗